Adenosine derivative in polymorph I form

ABSTRACT

(2S,3S,4R,5R)-2-(5-tert-butyl-[1,3,4]-oxadiazol-2-yl)-5-[6-(4-chloro-2-fluorophenylamino)-9H-purin-9-yl]-tetrahydrofuran-3,4-diol in polymorphic form.

[0001] The present invention relates to heterocyclyl substitutedadenosine derivatives. More particularly the invention is concerned witha particular physical form of(2S,3S,4R,5R)-2-(5-tert-butyl-[1,3,4]-oxadiazol-2-yl)-5-[6-(4-chloro-2-fluorophenylamino)-9H-purin-9-yl]-tetrahydrofuran-3,4-diol,pharmaceutical formulations thereof and its use in therapy.

[0002] WO99/67262 (Glaxo Group Limited) discloses certain heterocyclyladenosine derivatives including(2S,3S,4R,5R)-2-(5-tert-butyl-[1,3,4]-oxadiazol-2-yl)-5-[6-4-chloro-2-fluorophenylamino)-9H-purin-9-yl]-tetrahydrofuran-3,4-diol,Example 14 of WO99/67262, the structure of which is indicated below asthe compound of formula (A):

[0003] The preparation of the compound of formula (A) is described inWO99/67262. The compound of formula (A) may be prepared by the reactionof 4-chloro-2-fluoroaniline with an appropriate purinyl derivativehaving a suitable leaving group in the 6-position of the purine ring,optionally in the presence of a solvent at elevated temperatures.Alternatively the compound of formula (A) may be prepared by treating9-{(3aR,4R,6S,6aR)-6-[5-tert-butyl-1,3,4-oxadiazol-2-yl]-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl}-N-(4-chloro-2-fluorophenyl)-9H-purin-6-aminewith trifluoroacetic,acid followed by treatment with sodium bicarbonate.Extraction of the product into ethyl acetate followed by evaporation invacuo provides the compound of formula (A) as a buff solid.

[0004] We have now surprisingly found that the compound of formula (A)can be obtained in polymorphic forms.

[0005] There is thus provided as a first aspect of the invention(2S,3S,4R,5R)-2-(5-tert-butyl-[1,3,4]-oxadiazol-2-yl)-5-[6-(4-chloro-2-fluorophenylamino)-9H-purin-9-yl]-tetrahydrofuran-3,4-diolin polymorphic form.

[0006] We have found that the compound of formula (A) may be obtained bycrystallisation under certain conditions in the form of polymorphic formI (hereinafter Polymorph I).

[0007] There is thus provided in a further aspect of the invention(2S,3S,4R,5R)-2-5-tert-butyl-[1,3,4]-oxadiazol-2-yl)-5-[6-(4-chloro-2-fluorophenylamino)-9H-purin-9-yl]-tetrahydrofuran-3,4-diolas Polymorph I.

[0008] Polymorph I exhibits particular stability at ambienttemperatures, for example 15-200° C.

[0009] Polymorph I is easy to handle and particularly easy to process ona large scale and thus is useful in the preparation of pharmaceuticalformulations.

[0010] In a preferred aspect the invention provides(2S,3S,4R,5R)-2-(5-tert-butyl-[1,3,4]-oxadiazol-2-yl)-5-[6-(4-chloro-2-fluorophenylamino)-9H-purin-9-yl]-tetrahydrofuran-3,4-diolin the form of Polymorph I as herein defined substantially free of anyother polymorph.

[0011] In a further preferred aspect the invention(2S,3S,4R,5R)-2-(5-tert-butyl-[1,3,4]-oxadiazol-2-yl)-5-[6-(4-chloro-2-fluorophenylamino)-9H-purin-9-yl]-tetrahydrofuran-3,4-diolin the form of Polymorph I as herein defined substantially free ofimpurities.

[0012] By “substantially free” is meant containing less than 10%,preferably less than 5%, more preferably less than 2%, of alternativepolymorph or impurity.

[0013](2S,3S,4R,5R)-2-(5-tert-Butyl-[1,3,4]-oxadiazol-2-yl)-5-[6-(4-chloro-2-flurophenylamino)-9H-purin-9-yl]-tetrahydrofuran-3,4-diolmay be prepared in polymorphic form by crystallisation of the compoundunder suitable conditions.

[0014] Polymorph I may be prepared substantially free from alternativepolymorph by controlling crystallisation conditions.

[0015] In general,(2S,3S,4R,5R)-2-5-tert-butyl-[1,3,4]-oxadiazol-2-yl)-5-[6-(4-chloro-2-fluorophenylamino)-9H-purin-9-yl]-tetrahydrofuran-3,4-diolin the form of Polymorph I may be obtained by crystallisation of thecompound by heating in N,N-dimethylformamide at a temperature sufficientto effect dissolution, for example 70-90° C., initiating crystallisationby controlled addition of water until turbidity results, and allowing tocool to ambient temperature, for example 15-25° C.

[0016] Alternatively, Polymorph I is obtained by dissolving(2S,3S,4R,5R)-2-(5-tert-butyl-[1,3,4]-oxadiazol-2-yl)-5-[6-(4-chloro-2-fluorophenylamino)-9H-purin-9-yl]-tetrahydrofuran-3,4-diolin N,N-dimethylformamide/water in a ratio of 3.5:1 to 2.5:1, preferably3:1, optionally treating with decolourising charcoal, and cooling toless than 30° C., preferably 20-25° C., adding water and stirring theslurry prior to collecting the solid.

[0017] In a further alternative preparation Polymorph I may be preparedby dissolving(2S,3S,4R,5R)-2-(5-tert-Butyl-[1,3,4]-oxadiazol-2-yl)-5-[6-(4-chloro-2-fluorophenylamino)-9H-purin-9-yl]-tetrahydrofuran-3,4-diolin N,N-dimethylformamide and water wherein theN,N-dimethylformamide:water ratio is from 3.5:1 to 2.5:1, optionallytreating with decolourising charcoal, and either cooling to less than25° C. or cooling to less than 30° C. and seeding with polymorph I; andoptionally adding toluene prior to collection of the solid.

[0018] Interconversion of one polymorph to another can occur undercertain circumstances.

[0019] The methods for the preparation of polymorphic material, and inparticular methods for the preparation of Polymorph I, described hereinconstitute further aspects of the present invention.

[0020] Polymorph I has been characterised by X-ray powder diffraction(XRPD) studies and Raman spectroscopy.

[0021] Polymorph I is characterised by having peaks in its Raman spectraat 3429, 3414 and 76 cm⁻¹.

[0022] Raman peaks are quoted to the nearest cm−1.

[0023] Polymorph I is characterised by having an XRPD pattern withsignals at 4.32, 4.99, 6.23, 6.97, 8.64, 10.04, 12.53, and 14.47(degrees 2-theta).

[0024] The skilled person will recognise that XRPD peak positions areaffected by differences in sample height. The peak positions quotedherein are thus subject to a variation of +/−0.15 degrees 2-theta.

[0025] This invention further provides for a pharmaceutical compositioncomprising(2S,3S,4R,5R)-2-(5-tert-butyl-[1,3,4]oxadiazol-2yl)-5-[6-(4-chloro-2-fluorophenylamino)-9H-purin-9-yl]-tetrahydrofuran-3,4-diolin polymorphic form, and a pharmaceutically acceptable carrier and/orexcipient.

[0026] Suitable pharmaceutically acceptable carriers and excipients aredescribed in WO 99/967262.

[0027](2S,3S,4R,5R)-2-(5-tert-Butyl-[1,3,4]-oxadiazol-2-yl)-5-[6-(4-chloro-2-flurophenylamino)-9H-purin-9-yl]-etrahydrofuran-3,4-diolin polymorphic form may be used for decreasing plasma free fatty acidconcentration; reducing heart rate; or treating ischemic heart disease,peripheral vascular disease, stroke, pain, CNS disorder, or sleepapnoea, as described in WO 99/67262.

[0028](2S,3S,4R,5R)-2-(5-tert-Butyl-[1,3,4]-oxadiazol-2-yl)-5-[6-(4-chloro-2-flurophenylamino)-9H-purin-9-yl]-tetrahydrofuran-3,4-diolin polymorphic form may be used in the manufacture of a medicament foruse in decreasing plasma free fatty acid concentration; reducing heartrate; or treating ischemic heart disease, peripheral vascular disease,stroke, pain, CNS disorder, or sleep apnoea, as described in WO99/67262.

[0029] WO 99/67262 (Glaxo Group Limited) is incorporated by referenceherein as though fully set forth.

[0030] The following examples illustrate the invention but are notintended as a limitation thereof.

EXAMPLES

[0031](2S,3S,4R,5R)-2-(5-tert-Butyl-[1,3,4]oxadiazol-2-yl)-5-[6-(4-chloro-2-flurophenylamino)-9H-purin-9-yl]-tetrahydrofuran-3,4-diolwas prepared according to the methods described in WO99/67262.

Example 1 Preparation of Polymorph I

[0032](2S,3S,4R,5R)-2-(5-tert-Butyl-[1,3,4]oxadiazol-2-yl)-5-[6-(4-chloro-2-flurophenylamino)-9H-purin-9-yl]-tetrahydrofuran-3,4-diol(1 g) was taken up in N,N-dimethylformamide (DMF, 5 mL) and the mixtureheated to 70° C. to effect dissolution. Water was added at thistemperature until tubidity occurred (5 mL). The solution was then cooledto ambient (crystallisation ensued at ca. 50° C.) and allowed to standfor 1 hour before being filtered and the solid washed with water (1×2mL). The wet cake was dried in vacuo at ambient temperature. Yield: 85%.

Example 2 Preparation of Polymorh I

[0033](2S,3S,4R,5R)-2-(5-tert-butyl-[1,3,4]-oxadiazol-2-yl)-5-[6-(4-chloro-2-flurophenylamino)-9H-purin-9-yl]-tetrahydrofuran-3,4-diol(20.0 g) was dissolved in 3:1 DMF/water (266 mL), decolourising charcoal(5.0 g) added and the suspension heated at 60° C. for 1 hour. Thecharcoal was removed by filtration, the filter washed with 3:1 DMF/water(88 mL) and the filtrate cooled to 22-25° C. Water (44 mL) was added at22-25° C. and the slurry stirred overnight. Water (132 mL) was added,stirring continued for 2 hours and the product collected by filtration,washed consecutively with aqueous DMF and water and then dried in vacuoat 40° C. to give Polymorph I as an off white solid (16.3 g, 81%recovery).

[0034] X-Ray Powder Diffraction

[0035] The sample preparation and acquisition conditions were asfollows:

[0036] Samples were lightly ground and packed into silicon cup with a 12mm (diameter)×0.5 mm cavity. Data were acquired using a Bruker D8Advance X-Ray diffractometer configured with a Cu anode, primary andsecondary Soller slits, secondary monochromator and scintillationcounter. The generator was operated at 40 kV 40 mA. Variable divergenceand antiscatter slits were set at 12 mm irradiated area, and thedetector slit was set at 0.1 mm. A locked coupled step scan with 0.02degrees 2-theta step was used. The sample was rotated.

[0037] Data obtained for Polymorph I are shown in Figure I.

[0038] Raman Spectroscopy

[0039] Raman spectra were acquired using a Nicolet 960 ESP FT-Ramanspectrometer. Samples were held in glass vials; spectra of 5 differentpoints on a sample were averaged. Data collection parameters include:Laser power: 400 mW, Resolution: 4 cm−¹, Sample gain: 1.0, Detector:InGaAs, Beamsplitter: CaF2, Correction: none, Zero filling: none,Apodization: Happ-Genzel, Phase correction: Power spectrum.

[0040] A Raman spectrum of Polymorph I are shown in FIG. 2.

[0041] A photographic image of Polymorph I is shown in FIG. 3.

[0042] The application of which this description and these claims form apart may be used as a basis for priority in respect of any subsequentapplication. The claims of such subsequent application may be directedto any novel feature or combination of features relating to theinvention described herein. They may take the form of product, processor use claims and may include, by way of example and without limitation,the claims that follow.

1. (2S,3S,4R,5R)-2-(5-tert-Butyl-[1,3,4]-oxadiazol-2-yl)-5-[6-(4-chloro-2-fluorophenylamino)-9H-purin-9-yl]-tetrahydrofuran-3,4-diol in polymorphic form.
 2. A polymorphic form according to claim 1 wherein the polymorphic form is Polymorph I.
 3. A pharmaceutical formulation comprising a polymorphic form according to claim 1 or claim 2, and a pharmaceutically acceptable carrier and/or excipient.
 4. A polymorphic form according to claim 1 or claim 2 for use in decreasing plasma free fatty acid concentration; reducing heart rate; or treating ischemic heart disease, peripheral vascular disease, stroke, pain, CNS disorder, or sleep apnoea.
 5. Use of a polymorphic form according to claim 1 or claim 2 in the manufacture of a medicament for use in decreasing plasma free fatty acid concentration; reducing heart rate; or treating ischemic heart disease, peripheral vascular disease, stroke, pain, CNS disorder, or sleep apnoea.
 6. (2S,3S,4R,5R)-2-(5-tert-butyl-[1,3,4]-oxadiazol-2-yl)-5-[6-(4-chloro-2-fluorophenylamino)-9H-purin-9-yl]-tetrahydrofuran-3,4-diol in polymorphic form substantially as described herein in the specification and/or examples. 